Cyclic AMP-induced reversible EPAC1 condensates regulate histone transcription

Abstract The second messenger 3',5'-cyclic adenosine monophosphate (cAMP) regulates many nuclear processes including transcription1,2, pre-mRNA splicing3 and mitosis4. While most functions are attributed to protein kinase A (PKA)5,6, accumulating evidence suggests that not all nuclear cAMP-dependent effects are mediated by this kinase7, implying that other effectors are involved. Here we explore the nuclear roles of Exchange Protein Activated by cAMP 1 (EPAC1). We find that EPAC1 enters the nucleus through the synergy of two aminoacidic domains and there, in response to cAMP, forms reversible biomolecular condensates through liquid-liquid phase separation. This phenomenon depends on intrinsically disordered regions present at its amino-terminus and is independent of PKA. Finally, we demonstrate that nuclear EPAC1 condensates assemble at genomic loci on chromosome 6 and promote the transcription of a histone gene cluster. Collectively, our data reveal an unexpected mechanism through which cAMP contributes to nuclear spatial compartmentalization and promotes the transcription of specific genes.